Monday, April 30, 2012

Form and Function: Architecture of the Brain

I recently wrote a News & Views article for the journal Nature Neuroscience.
It was my first primary-author paper as a grad student and I'm super
excited about it. However, it's hard to share this with all my friends
and family because 1) the article is behind a paywall, and 2) it was
written for neuroscientists, not a general audience. So, I've decided
to present a simplified, free version here! If you want to check out
the actual article, as well as the original research that is summarized,
they're both available on the Nature Neuroscience website.

To
put the topic of the article in the most extremely generalized way
possible: What can we tell about something from how it looks?

Examples of neuronal architecture, as drawn by Santiago Ramon y Cajal, the father of neuroanatomy

Form & Function

We
can examine the teeth of a great white shark and assume that it's a
vicious predator. Or we can see a giraffe's long neck and suspect that
it needs to reach high places to survive. Structure often gives us many clues about function. And this is true in neuroscience too. A
neuron with a broad, elaborate arbor of processes (see right) is more likely to
receive and integrate diverse information than a neuron with only a few
simple processes.

However, the story of form &
function is usually much more complicated. Especially when dealing with
heterogeneous populations -- groups of neurons with distinct properties
all living together in the same area. This is troublesome because the
technique we usually use for assessing neuronal activity during
functionally-important times (like during a specific behavior) involves
sticking an electrode semi-blindly into a living brain and listening to
the chatter of all the neurons in a certain area. It's extremely
difficult to make connections between neuronal activity in a living
animal and detailed structural data obtained from dead brain slices.

The Dopamine Puzzle

This
was the challenge taken on by Pablo Henny and his colleagues at Oxford,
who approached the problem with a combination of technical prowess and
brute force. The brain area they chose to investigate was the substantia
nigra pars compacta, or SNc. This is the home of neurons that produce
dopamine, a chemical responsible for feelings of reward and motivation.
Most drugs of abuse hijack the dopamine system, and the hallmark of
Parkinson's disease is a loss of dopaminergic neurons in the SNc. For
researching form and function in the brain, the SNc is a great place to
start.

Dopamine neurons (image from reprocell.com)

Neurons in the SNc are also a great example of a tricky
heterogeneous population. Researchers had previously found that
individual SNc neurons exhibit varying responses to different kinds of
stimuli. So for example, when a rat's tail is pinched, some cells
increase their activity, while others get quieter. But no one really
understood how or why these different patterns of activity occurred.

Connecting the Dots

Henny
and colleagues devised the following solution. First, they stuck
electrodes into the brains of living rats and recorded the activity of
SNc neurons during an aversive stimulus (a tail pinch). Then they used a
technique called juxtacellular labeling, which fills the neuron next to
the electrode with a dye that can be imaged later. Now they had single
neurons whose functional activity was known, and they could do detailed
analyses (once the brain was sliced up) of the structural and
anatomical properties of each individual neuron.

The results of
their study are summarized in the figure below. Looking at the
anatomical structure, Henny and colleagues found that SNc neurons vary
in how much of their processes extend into an adjacent region called the
SNr. They also labelled excitatory and inhibitory inputs onto each
cell and found that processes in the SNr received more inhibition. When
they compared this to the response to the tail pinch, they discovered
that cells with more processes in the SNr are more likely to exhibit a
decrease in activity. Which is exactly what you'd expect, since these
cells are receiving more inhibitory inputs.

Dopamine neurons of the SNc that extend further into the SNr receive more inhibition and are therefore more likely to respond to a specific stimulus by decreasing their activity

Beyond Dopamine

The current study is an impressive demonstration of a thorough analysis of form
and function. The technical prowess of this work is that they do a
beautiful job
filling and imaging neurons. And the brute force aspect is that they
had to do this for LOTS of cells in order to actually draw conclusions
rather than simply reporting isolated observations. These results give us
new insight into the brain's dopamine system -- a system of particular
interest because of its role in so many behaviors and diseases.

But
beyond this, similar techniques can be used to investigate many other
brain areas with heterogeneous neuronal populations. We can make new connections
between what a neuron looks like, in terms of its static anatomical
structure in a dead brain slice, and what it does functionally in a
living animal. The doors are wide open for unraveling new information from the architecture
of the brain.

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About Me

I'm a neuroscience PhD with a background in biomedical engineering who's now working as a science writer specializing in oncology. I love being creative and communicating science to other people, and here's where I get to do it for fun!